PAX2, a paired domain transcription factor, is mitogenic and blocks apoptosis in nephrogenic sem cells during kidney development. We have recently demonstrated PAX2 expression in putative stem cells of normal human mammary epithelium. We have also found PAX2 in >50% of the breast tumor samples investigated (n=38). Functional analyses, using mouse mammary glands in which PAX2 has been ablated, revealed inhibition of progesterone-stimulated growth, as well as reduced expression of critical anti-apoptosis genes, including bcl-2. Our finding of PAX2 expression in the mammary gland is completely novel and has broad implications for understanding the control of differentiation and the abnormal de-differentiation of breast cancer. Based on our preliminary findings, we hypothesize that PAX normally participates in the regulation of the mammary progesterone response and PAX2 over-expression abnormally inhibits apoptosis, possibly contributing to mammary tumorigenesis. We propose to exploit PAX2-null mammary tissue lines, as well as specially developed transgenic mice over-expressing mammary-targeted PAX2, to pursue the following Specific Aims: 1. Characterize growth, morphogenesis and apoptosis in PAX2-null mammary glands. 2. Investigate the mechanisms underlying inhibition of progesterone- stimulated growth in PAX2-null mammary glands. 3. Investigate the influence of PAX2 over-expression on mammary apoptosis. 4. Investigate the effects of PAX2 over-expression on mammary tumorigenesis. The results of these investigations will define the role of PAX2 in the progesterone-signaling pathway in the mammary gland. Over-expression of PAX2 contributes to kidney proliferative disease by persistently blocking apoptosis. It is anticipated that the proposed experiments will contribute to defining a similar role for PAX2 in breast cancer, ultimately suggesting ways to reverse this abnormality and stimulate breast tumor cell death. Finally, the possibility that PAX2 is a mammary tumor promoter will be evaluated, providing insights into mechanisms of breast cancer progression.